Evaluation of disease-free survival as a predictor of overall survival and assessment of real-world burden of disease recurrence in resected early-stage non–small cell lung cancer

BACKGROUND: Intermediate endpoints, such as disease-free survival (DFS), have shown good correlation with overall survival (OS) in early-stage non–small cell lung cancer (NSCLC) clinical trials. However, real-world data are limited, and no previous real-world study has quantified the clinical and economic burden of disease recurrence. OBJECTIVE: To examine the association between real-world DFS (rwDFS) and OS and quantify the association between NSCLC recurrence and health care resource utilization (HCRU), health care costs, and OS in patients with resected early-stage NSCLC in the United States. METHODS: Data from the Surveillance, Epidemiology, and End Results–Medicare database (2007-2019) for patients with newly diagnosed stage IB (tumor size ≥ 4 cm) to IIIA (American Joint Committee on Cancer 7th edition) NSCLC who underwent surgery for primary NSCLC were analyzed in this retrospective observational study. Baseline patient demographic and clinical characteristics were described. rwDFS and OS were compared between patients with vs without recurrence using Kaplan-Meier curves and the log-rank test; their correlation was assessed using normal scores rank correlation. All-cause and NSCLC-related HCRU and health care costs were summarized, and mean monthly allcause and NSCLC-related health care costs were compared between cohorts using generalized linear models. RESULTS: Of the 1,761 patients who underwent surgery, 1,182 (67.1%) had disease recurrence; these patients had shorter OS from the index date and shorter subsequent OS at each postsurgery landmark (ie, 1, 3, and 5 years) than those without recurrence (all P < 0.001). OS and rwDFS were significantly correlated (0.57; P < 0.001). Patients with recurrence also had significantly higher all-cause and NSCLC-related HCRU and mean monthly all-cause and NSCLC-related health care costs during the study period. CONCLUSIONS: Postsurgery rwDFS was significantly correlated with OS in patients with early-stage NSCLC. Patients with postsurgery recurrence had a higher risk of death and incurred higher HCRU and health care costs than those without recurrence. These findings highlight the importance of preventing or delaying recurrence in patients with resected NSCLC.


Correlation between DFS and OS and burden of recurrence in resected early-stage NSCLC
This retrospective observational study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data to examine the association between real-world DFS (rwDFS) and OS and quantify the association between NSCLC recurrence and HCRU, health care costs, and OS in patients with resected early-stage NSCLC in the United States.

STUDY DESIGN AND DATA SOURCE
Patients with newly diagnosed stage IB (tumor size ≥ 4 cm)-IIIA (AJCC 7th edition) NSCLC were selected from the SEER-Medicare database (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019). The database links data from 2 sources-namely, SEER cancer registries (containing clinical and demographic information and cause of death) and Medicare insurance claims for health care services used by beneficiaries from the time of eligibility until death. As of August 2022, the database included all Medicare-eligible persons in the SEER registry diagnosed with cancer through 2017 and their Medicare claims through 2019. Information on Medicare drug coverage (Part D) was available starting from 2007. All data were limited and adhered to the Health Insurance Portability and Accountability Act and Declaration of Helsinki.
The study sample consisted of patients who underwent surgery for primary lung cancer with or without adjuvant chemotherapy and who did not receive chemotherapy in the neoadjuvant setting or adjuvant radiotherapy. The index date for patients with recurrence was defined as the date 30 days before the record of recurrence to capture claims in the study period that were likely recurrence-related but occurred before recurrence was observed in the claims data. 15,16 For patients without recurrence, the index date was a randomly selected date based on the distribution of time between the first surgery and recurrence in patients who experienced a recurrence. The baseline period was the 12 months preceding the index date, and the follow-up period was the time from the index date to the earliest among end of data availability, end of enrollment, and death (Supplementary Figure 1, available in online article). Patients had to have undergone their first surgery for NSCLC before 2015 to ensure a theoretical minimum follow-up of 5 years (from date of primary surgery to data cutoff).

STUDY POPULATION
The flow diagram of patient selection is shown in Figure 1. Inclusion criteria were as follows: (1) record of a NSCLC diagnosis in the SEER registry between 2007 and 2017 based on International Classification of Diseases for Oncology, Third Edition codes 340 -C343, C348, and C349 and relevant histology codes (8010, 8012, 8013, 8020, 8046, 8050 -8052, with early-stage NSCLC. Patients with postsurgery recurrence had a higher risk of death and incurred higher HCRU and health care costs than those without recurrence. These findings highlight the importance of preventing or delaying recurrence in patients with resected NSCLC. Lung cancer is one of the most common and deadly cancers in the United States. The American Cancer Society projects approximately 230,000 lung cancer diagnoses and more than 130,000 deaths from the disease in 2023. 1 Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 85% of cases. 2 The management of NSCLC varies by disease stage. The standard primary treatment is radical surgery followed by up to 4 cycles of adjuvant therapy with a platinum-based doublet for patients with resectable stage II-IIIA (American Joint Committee on Cancer [AJCC] 7th edition) disease. 3,4 Patients with resectable stage IB (AJCC 7th edition) disease with tumors 4 cm or larger or other high-risk factors are treated with a similar approach as patients with stage II-IIIA disease. 5 The treatment landscape in the adjuvant setting has dramatically evolved with the advent of novel treatments, including targeted therapy and immunotherapy. In the United States, atezolizumab and osimertinib have been approved for adjuvant therapy after resection in patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on at least 1% of tumor cells in 2021 and in patients with NSCLC whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 L858R mutations in 2020, respectively. 6,7 Pembrolizumab was approved in 2023 for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC. 8 Given the prolonged timeline and significant costs associated with demonstrating overall survival (OS) benefit in early-stage cancer, intermediate endpoints, such as disease-free survival (DFS), have been used as primary endpoints in clinical trials of adjuvant therapies for earlystage NSCLC. [9][10][11] A positive correlation between DFS and OS in early-stage NSCLC has been demonstrated using clinical trial data 12 ; however, there is no such evidence from real-world studies.
Although health care resource utilization (HCRU) and health care costs associated with NSCLC have been documented, 13,14 there have been few studies on the economic burden and OS associated with recurrence in early-stage NSCLC in a real-world patient population. As the treatment landscape for early-stage NSCLC evolves, such evidence is needed to evaluate clinical and economic impact of novel therapies that can potentially prevent or delay recurrence and improve patient outcomes.
Correlation between DFS and OS and burden of recurrence in resected early-stage NSCLC adjuvant radiotherapy; and (5) had no diagnoses of distant secondary malignancies before or within 30 days after surgery. Patients with health maintenance organization coverage anytime during the study period were excluded.
Patients who met the inclusion criteria were assigned to the recurrence or nonrecurrence cohort. Recurrence after surgery (including locoregional recurrence and distant metastasis) was defined as a diagnosis of metastatic disease, new diagnosis of locoregional disease, and/or any additional treatments for NSCLC (including additional surgery, radiotherapy, chemoradiation, and systemic therapy) following a 90-day treatment-free interval starting immediately after the initial surgery. Adjuvant chemotherapy, which was

n = 3,112
Without a diagnosis of metastatic disease, new diagnosis of locoregional disease, or any additional treatments for NSCLC following a 90-day treatment-free interval after initial surgery. Underwent initial surgery for NSCLC before 2015 n = 1,182 N = 587,307 Stage IB-IIIA NSCLC, as defined by combined pathologic and clinical TNM stage, and aged ≥66 years and with ≥12 months of Medicare eligibility at initial diagnosis.

n = 62,091
No other cancers before initial diagnosis of NSCLC; continuously enrolled in Medicare Parts A, B, and D ≥12 months after initial diagnosis.

n = 10,927
Underwent either a lobectomy or a pneumonectomy within 6 months after initial diagnosis; no prior neoadjuvant or adjuvant radiotherapy or neoadjuvant chemotherapy.

n = 3,562
No diagnoses of distant secondary malignant neoplasms prior to or within 30 days after surgery.

Recurrence cohort
With a diagnosis of metastatic disease, new diagnosis of locoregional disease, or any additional treatments for NSCLC following a 90-day treatment-free interval after initial surgery.

n = 2,015
Continuous enrollment in Medicare from initial diagnosis (or ≥12 months before the index date, whichever was longer) to ≥6 months after the index date.

n = 1,557
Continuous enrollment in Medicare from initial diagnosis (or ≥12 months before the index date, whichever was longer) to ≥6 months after the index date.

Correlation between DFS and OS and burden of recurrence in resected early-stage NSCLC
chi-square test for categorical variables. OS was described using Kaplan-Meier curves and was compared between the recurrence and nonrecurrence cohorts with the log-rank test. Cox proportional hazards models adjusted for key baseline characteristics, including disease stage at diagnosis (AJCC 7th edition staging), histologic type, age at surgery, sex, race, Charlson Comorbidity Index (CCI), and use of adjuvant chemotherapy. Landmark analyses of OS were performed at 3 time points (ie, 1, 3, and 5 years postsurgery). Subsequent OS was described and compared between patients with and those without recurrence at landmark time points using Kaplan-Meier curves and Cox proportional hazards models adjusted for key baseline characteristics. The correlation between rwDFS and OS was assessed by normal scores rank correlation. PPPM IRs of all-cause and NSCLCrelated HCRU were compared between patients with and without recurrence using generalized linear models with a negative binomial distribution and log-link function. Offset terms were included in the models to account for different follow-up durations. IR ratios (IRRs) comparing outcome measures between the 2 cohorts were reported with corresponding 95% CIs and P values. Mean monthly all-cause and NSCLC-related health care costs per patient were compared between patients with and without recurrence using generalized linear models with a Tweedie distribution and log-link function. For both HCRU and health care costs, the covariates were age at index date, sex, race, region, CCI, histology, disease stage at diagnosis (AJCC 7th edition staging), and number of all-cause inpatient and outpatient visits PPPM during the baseline period.

Results
Overall, 1,761 patients with early-stage NSCLC who underwent surgical resection of the primary tumor, including 1,182 (67.1%) patients with disease recurrence, met the study inclusion criteria (Figure 1). The median follow-up time was 55.0 months from the first surgery date to death, the last date of follow-up in SEER-Medicare data, and end of data availability, whichever was earliest.

BASELINE CHARACTERISTICS
The mean age at the index date was approximately 75 years; around half of the patients were male, and 84% in both cohorts were White (Table 1). A smaller proportion of patients in the recurrence cohort were diagnosed with stage IB (tumor size ≥ 4 cm) and a higher proportion had stage IIIA NSCLC compared with the nonrecurrence cohort (P < 0.001). More than half of the patients in both cohorts had nonsquamous disease at initial diagnosis. The proportion of patients who received adjuvant chemotherapy was larger defined as any US Food and Drug Administration-approved or National Comprehensive Cancer Network-recommended adjuvant treatment initiated within 90 days after the surgery, was permitted during the 90 -day treatment-free interval. For patients who received adjuvant treatment, the following 2 events were further considered to identify recurrence: (1) initiation of a new regimen at least 30 days after the start of adjuvant treatment; (2) reinitiation of the same regimens at least 90 days after the end of adjuvant treatment.

STUDY MEASURES AND OUTCOMES
Baseline patient demographic and clinical characteristics were collected. Clinical outcomes were rwDFS and OS. rwDFS was defined as the time from the initial surgery for NSCLC to first recurrence or death, whichever occurred first. For analyses of the burden associated with disease recurrence, OS was defined as the time from the index date to death. For the analysis of the correlation between OS and rwDFS, OS was defined as the time from the initial surgery to death. In the landmark analysis assessing the association between OS and rwDFS, OS was defined as the time from a predetermined landmark time point (ie, 1, 3, and 5 years postsurgery, respectively) to death. For all outcomes, patients were censored at the earlier of the last date of follow-up in the SEER-Medicare data and end of data availability. All-cause NSCLC-related HCRU and health care costs were determined based on claims for medical services or for the administration of antineoplastic treatments associated with a diagnosis for NSCLC. Specifically, a claim was considered NSCLC-related if there was a primary diagnosis of NSCLC for an outpatient visit. For other types of visit, a primary or a secondary diagnosis of NSCLC was used to determine whether the claim was NSCLC-related. All-cause and NSCLC-related HCRU outcomes were summarized as incidence rate (IR) per patient per month (PPPM), defined as the ratio between total number of events and total person-months during the follow-up period to account for variable lengths of follow-up in the study period across individual patients. NSCLC-related costs were costs associated with NSCLC-related HCRU, including medical costs and NSCLC-related Part D pharmacy costs. All costs were inflated to 2021 US dollars using the personal consumption expenditures medical care component. 18

STATISTICAL ANALYSIS
Baseline characteristics were described and compared between patients with and without recurrence. Means and SDs are reported for continuous variables, and frequency counts and percentages are reported for categorical variables. Statistical comparisons between the 2 cohorts were performed with the t-test for continuous variables and the months; P < 0.001) (Figure 2), and the OS rate of the recurrence cohort remained consistently lower during the followup period. The Cox adjusted hazard ratio indicated a 3.72 times higher risk of death for patients with recurrence compared with those without recurrence (95% CI = 3.11 -4.45; P < 0.001).

LANDMARK ANALYSES AND CORRELATION BETWEEN rwDFS AND OS
At each postsurgery landmark time point, patients with recurrence had significantly shorter subsequent OS than those without recurrence (Supplementary Figure 2). At the 1 -, 3 -, and 5 -year landmarks, the median OS was 29.3, 42.3, and 43.4 months, respectively, for patients with recurrence and 77.9, 79.6, and 72.0 months, respectively, for patients without recurrence (all P < 0.001) ( The estimated normal scores rank correlation of 0.58 indicated that there was a statistically significant correlation between rwDFS and OS (95% CI = 0.54, 0.62; P < 0.001).

HCRU AND COSTS ASSOCIATED WITH NSCLC RECURRENCE
Compared with patients without recurrence, those in the recurrence cohort had significantly higher HCRU during the study period (Table 3)

OS OF PATIENTS WITH VS WITHOUT RECURRENCE
The OS from the index date was significantly shorter for patients with recurrence than for those without recurrence (median OS, 33.5 vs 108.4 in the recurrence cohort (45.6% vs 30.4%; P < 0.001). Patients with recurrence were also younger at the time of surgery (mean age, 73.5 vs 74.5 years; P = 0.001) and had a higher CCI (1.9 vs 1.7; P = 0.016) than those without recurrence. In terms of baseline HCRU, patients in the recurrence cohort had a higher number of all-cause outpatient visits (2.6 vs 2.4; P = 0.001) but  and days hospitalized (0.9 vs 0.3 days PPPM; aIRR = 4.16; 95% CI = 3.53 -4.91; P < 0.001). The greatest differences in NSCLC-related HCRU between cohorts were for inpatient admissions (0.1 vs 0.0 admissions vs 0.2 visits PPPM; aIRR = 6.73; 95% CI = 6.09 -7.45; P < 0.001). Accordingly, patients in the recurrence cohort incurred significantly higher health care costs than those in the nonrecurrence cohort (Table 3). In particular, adjusted monthly cost differences for mean all-cause total costs and mean NSCLC-related costs were $4,204 and $2,671, respectively (both P < 0.001); this implies a potential reduction over 5 years of up to $252,240 per patient in all-cause health care costs, assuming a 5-year delay in disease recurrence.  20 We also assessed the correlation between rwDFS and OS following surgery in patients with early-stage NSCLC. To the best of our knowledge, this is the first study to analyze this correlation using a real-world dataset. The results showed that at each postsurgery landmark time point, patients with recurrence had significantly shorter subsequent OS  Correlation between DFS and OS and burden of recurrence in resected early-stage NSCLC early-stage NSCLC. To address this gap, the present work compared HCRU and health care costs between patients with resected early-stage NSCLC with vs without recurrence. Recurrence was associated with significantly higher all-cause and NSCLC-related HCRU and costs during the study period. This implies that delaying disease recurrence by 5 years with appropriate and effective interventions can yield a saving of up to $252,240 per patient in all-cause health care costs.

Discussion
This study had important strengths. First, the linked SEER-Medicare database provided detailed clinical and demographic information and HCRU for a defined population of patients with resected early-stage NSCLC in the United States. Second, the comparison of OS provided a comprehensive view of the disease burden of patients with vs without recurrence. Third, the demonstration of a correlation between postsurgery rwDFS and OS in patients with early-stage NSCLC further supports the use of DFS to predict overall survival in future studies. than those without recurrence and that DFS and OS were positively correlated. The findings are consistent with those of previous analyses of clinical trial data demonstrating a correlation between surrogate survival endpoints and OS in patients with operable and locally advanced lung cancer. For example, a study evaluating DFS, progression-free survival, and locoregional control as potential surrogate endpoints using data for 15,071 patients enrolled in 60 randomized clinical trials concluded, based on a high level of evidence, that DFS is a valid surrogate endpoint for OS in studies of adjuvant chemotherapy involving patients with NSCLC. 12 The economic burden associated with advanced NSCLC has been investigated in other studies 13,14 ; a populationbased study comparing HCRU among patients with completely resected stage II-IIIB NSCLC who received adjuvant therapy between 2008 to 2017 at US Oncology Network clinics found that patients had more ED visits and hospitalizations after as compared with before recurrence. 21 However, there is limited information on the costs associated with NSCLC recurrence in patients with resected